Structural modification of ginsenoside Rh2 by fatty acid esterification and its detoxification property in antitumor

Ginsenoside Rh2, one of the most important ginsenosides with anticancer properties in red ginseng, has been developed as principal antitumor ingredient for clinical use. However, the cytotoxicity test in human hepatocyte cell line QSG-7701 (IC50 37.3 μM) indicated that Rh2 might show strong cytotoxic side-effect on the normal liver cells. For blunting the toxicity, Rh2 was structurally modified by reacting with octanoyl chloride to give a dioctanoyl ester of Rh2 (D-Rh2) in the present study. MTT assay in QSG-7701 cell line in vitro showed that the cytotoxicity of D-Rh2 on human hepatocyte cells (IC50 80.5 μM) was significantly lower than that of Rh2. While antitumor xenograft assay in mice bearing H22 liver cancer cells in vivo showed that the antitumor activity of D-Rh2 retained to be strong as that of Rh2. According to previous pharmacokinetic studies, the fatty acid esterification of Rh2 might be of detoxification reaction to cells. Additionally, D-Rh2 showed significant enhancement on increasing thymus index at the dose of 10 mg/kg compared with vehicle treated control group. Thus, D-Rh2 might indirectly affect tumor growth by stimulating lymphocytes to become cytotoxic to tumor cells. Finally, our findings suggested that D-Rh2, the fatty acid ester of Rh2, might attenuate the side-effect by detoxification to human normal cell and could be a more potential candidate for developing as an antitumor drug.